title: In situ blood-brain barrier permeability of a C-10 paclitaxel carbamate.
abstract: We report the synthesis and blood-brain barrier (BBB)-permeability of (14)C-CNDR-29, a paclitaxel C-10 carbamate derivative shown to be devoid of P-glycoprotein (Pgp)-interactions, in an in situ mouse brain perfusion model, in comparison with (14)C-paclitaxel. The results presented reveal a 3- to 4-fold higher BBB-permeability for the C-10 modified taxane compared to paclitaxel. These results support the notion that circumvention of Pgp-mediated efflux can lead to higher BBB-permeability. Further studies however are needed to evaluate the therapeutic potential of the C-10 carbamates paclitaxel derivatives for the treatment of CNS diseases.
authors.affiliation: Center for Neurodegenerative Diseases Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, USA. bcarlo@sas.upenn.edu
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002490:Central Nervous System / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D013329:Structure-Activity Relationship
chemical_list: C534103:(14)C-CNDR-29; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002219:Carbamates; D017239:Paclitaxel